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Aims: For over 30 years, combined research and treatment settings in the US have been critical to conceptualizing care for first‐episode psychosis (FEP). Here we describe an early example of such a context, the Services for the Treatment of Early Psychosis (STEP) clinic, which is affiliated with the University of Pittsburgh. Methods: We describe STEP's historical roots and establishment in the early 1990s; STEP's research and treatment contributions, alongside its growth and ongoing leadership. Results: Research‐based clinics, like STEP, preceded and helped pave the way for the Recovery After an Initial Schizophrenia Episode project in the US and the ensuing Coordinated Specialty Care (CSC) approach, now widely adopted in the US. Early clinic‐based research at STEP helped establish protocols for psychopharmacology, the relevance of effective early treatment, including psychosocial approaches, and highlighted disparities in treatment outcomes across race/ethnicity. Multidisciplinary collaboration and dialogue with consumers contributed to early treatment, combining psychosocial and pharmacological approaches. STEP adopted CSC and is situated within a bi‐state Learning Health System. STEP has retained a relatively unique 5‐year treatment model and exists within continuum of care ideally suited to studying psychotic illness and treatment outcomes. Conclusions: STEP remains the largest academic FEP clinic in Pennsylvania. Academic FEP clinics like STEP will have a critical role within Learning Health Systems nationally to model participatory approaches, sustain early intervention treatment quality and ongoing treatment developments. [ABSTRACT FROM AUTHOR]

Background: Past research has found that family involvement in psychosis treatment leads to better patient outcomes. Thus, caregiver communication skills training can be a viable approach to reducing caregiver stress and increasing self‐efficacy and communication. Aim: The purpose of this qualitative study was to describe family caregivers' perceptions of changes in themselves and their family member with psychosis following their participation in Motivational Interviewing in Loved Ones (MILO), a brief four to five‐hour psychoeducational intervention for caregivers. Methods: Sixty‐three participants in the MILO trials provided written qualitative responses to the prompt, "Since learning the ideas and techniques in this course, what is the most significant change you noticed in yourself, your family, or your relationships?" Responses were collected immediately following MILO participation and 12 weeks later. Qualitative themes were identified through an iterative consensus process. Results: Most participants reported positive changes in multiple domains of their lives. Major themes included: (1) Changes in Self, (2) Changes in Relationships, (3) Changes in Mindset, (4) Use of MILO Skills, and (5) Challenges. Conclusion: Qualitative results support and add context to the previously reported quantitative results from this study. MILO is a promising family intervention that positively influenced family environment and communication in pilot trials. Adaptations of MILO for families outside of a highly educated North American context should be considered. [ABSTRACT FROM AUTHOR]

Aim: Early interventions are well understood to improve psychosis outcomes, but their successful implementation remains limited. This article introduces a three‐step roadmap for advancing the implementation of evidence‐based practices to operate as a learning health system, which can be applied to early interventions for psychosis and is intended for an audience that is relatively new to systematic approaches to implementation. Methods: The roadmap is grounded in implementation science, which specializes in methods to promote routine use of evidence‐based innovations. The roadmap draws on learning health system principles that call for commitment of leadership, application of evidence, examination of care experiences, and study of health outcomes. Examples are discussed for each roadmap step, emphasizing both data‐ and stakeholder‐related considerations applicable throughout the roadmap. Conclusions: Early psychosis care is a promising topic through which to discuss the critical need to move evidence into practice. Despite remarkable advances in early psychosis interventions, population‐level impact of those interventions is yet to be realized. By providing an introduction to how implementation science principles can be operationalized in a learning health system and sharing examples from early psychosis care, this article prompts inclusion of a wider audience in essential discourse on the role that implementation science can play for moving evidence into practice for other realms of psychiatric care as well. To this end, the proposed roadmap can serve as a conceptual guiding template and framework through which various psychiatric services can methodically pursue timely implementation of evidence‐based interventions for higher quality care and improved outcomes. [ABSTRACT FROM AUTHOR]

Aim: Expressed emotion of family members is a key target for intervention for bettering psychosocial outcomes for transitional‐age youth experiencing mental health crises. Motivational Interviewing for Loved Ones (MILO) seeks to reduce expressed emotion by teaching parents motivational interviewing skills such as taking a non‐judgmental stance, exploring their loved one's thoughts and feelings, expressing optimism and confidence, and avoiding taking an expert role. This report details the creation of the Motivational Interviewing for Loved Ones‐ Skills Assessment (MILO‐SA), its psychometric properties, and convergent validity with other measures of motivational interviewing adeptness. Methods: Our sample (n = 54) consisted of baseline assessments from parents participating in a pilot study of MILO. Parents were assessed for baseline knowledge of motivational interviewing as well as MILO skills with the MILO‐SA and a traditional assessment clinician application of motivational interviewing skills. Results: We found that the MILO‐SA displayed high interrater reliability (k = 0.81), and convergent validity with motivational interviewing knowledge (r = 0.32) as well as traditional assessments of clinician adeptness applying motivational interviewing skills (r = 0.67). Conclusions: Our findings suggest that the MILO‐SA has strong psychometric properties and is a useful tool for assessing parent acquisition of motivational interviewing skills. Specifically, the MILO‐SA can be used in future studies focused on teaching non‐clinicians motivational interviewing skills. [ABSTRACT FROM AUTHOR]

Aim: Although violent behaviour has been studied in schizophrenia, violence risk has received little attention in individuals at clinical high risk for psychosis (CHR). This manuscript aims to report and discuss the overall results of the Structured Assessment for Violence Risk in Youth (SAVRY) from the NAPLS‐3 project to explore the risk of violence in CHR youth and to determine the relationship between SAVRY violence risk scores, psychosis risk symptoms, and global functioning. We hypothesized that CHR young people are at higher risk of violence as compared to healthy comparison participants due to a similarity between risk factors for psychosis and risk factors for violence, and that this risk is associated with greater severity of symptoms, poor functioning, and risk for conversion to psychosis. Methods: Participants from the North American Prodrome Longitudinal Study consortium phase 3 (NAPLS‐3) included 684 CHR and 96 HC. Assessments included the Structural Assessment of Violence Risk in Youth (SAVRY), clinical and functional measures. Results: The majority of participants across groups were deemed to be at low risk for violence. There were significantly more CHR participants (29.8%) who had moderate or high scores on the SAVRY Summary Risk Rating compared to HC participants (3.1%). Low versus moderate‐high SAVRY scores were associated with better social (p <.005) and role (p <.002) functioning and fewer positive (p <.002), negative (p <.002), disorganized (p <.01) and general symptoms (p <.002). CHR participants with higher SAVRY scores were more likely to be diagnosed with borderline personality disorder, ADHD and substance misuse. Among CHR, overall violence risk was not associated with conversion to psychosis. However, those who converted to psychosis scored lower on the protective factors index, primarily driven by less prosocial involvement and fewer resilient personality traits. Conclusions: This is the first study to assess violence risk in CHR adolescents. Violence risk factors overlap with risk factors for psychosis in general, perhaps accounting for the association. These findings have implications for intervention efforts to reduce violence risk and bolster resiliency in CHR youth. [ABSTRACT FROM AUTHOR]

Aim: A large body of evidence demonstrates the importance of the family environment in the developmental trajectory of mental illness in young people. Caregiver communication skills training represents a potential model for influencing the outcomes of adolescents and young adults struggling with emerging mental health and behavioural difficulties. The aim of the current study is to describe the development of a telehealth group training intervention for caregivers of adolescents and young adults, and to report the results of a pilot feasibility‐effectiveness study that took place in 2020–2021. Methods: The "School of Hard Talks" intervention consisted of 8 h of training in communication skills consistent with motivational interviewing techniques. All pilot study participants were assigned to receive the intervention. Outcomes of interest were family conflict, caregiver stress, caregiver self‐efficacy and expressed emotion (EE). Participants were assessed three times: prior to the intervention, after the intervention and 12 weeks later. Results: A total of 62 participants enrolled in the study, of whom 49 completed the intervention. Large, significant improvements were observed over time in all four domains of interest. Qualitative feedback from parents was very positive and added context to quantitative observations. Conclusions: The School of Hard Talks was a feasible and effective intervention targeting both caregiver wellbeing as well as important mechanisms of risk for youth psychopathology, namely family conflict and EE. Further research involving a larger sample and a control condition are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Aim: Individuals at clinical high risk (CHR) for psychosis have been shown to experience more trauma than the general population. However, although the effects of trauma appear to impact some symptoms it does not seem to increase the risk of transition to psychosis. The aim of this article was to examine the prevalence of trauma, and its association with longitudinal clinical and functional outcomes in a large sample of CHR individuals. Methods: From the North American Prodrome Longitudinal Study‐3 (NAPLS‐3) 690 CHR individuals and 91 healthy controls from nine study sites between 2015 and 2018 were assessed. Historical trauma experiences were captured at baseline. Participants completed longitudinal assessments measuring clinical outcomes including positive and negative symptoms, depression, social and role functioning and assessing transition to psychosis. Results: From the 690 CHR participants and 96 healthy controls, 343 (49.6%) and 15 (15.6%), respectively, reported a history of trauma (p <.001). Emotional neglect (70.3%) was the most commonly reported type of trauma, followed by psychological abuse (57.4%). Among CHR participants, time to transition to psychosis was not associated with trauma. Baseline depression and suspiciousness/persecutory ideas were statistically significantly different between CHR individuals who did or did not experience trauma. However, when examining clinical and functional outcomes over 12‐months of follow‐up, there were no differences between those who experienced trauma and those who did not. Conclusion: Overall, trauma is a significantly prevalent among CHR individuals. The effects of trauma on transition and longitudinal clinical and functional outcomes were not significant. [ABSTRACT FROM AUTHOR]

Aim: Successful delivery of care to individuals with early psychosis depends on the ability of community providers to identify and refer appropriate candidates for services. Although specialty centres commonly rely upon education and outreach campaigns to building bridges with community providers, few studies have examined the effectiveness of these campaigns or the mechanisms by which they may achieve their intended effects. Methods: We surveyed community clinicians (N = 39) about their screening behaviours, referral practices, and confidence in managing early psychosis just before and 3–6 months after attending an educational event designed to promote recognition and quality treatment of early psychosis. Results: Three to six months following attendance, providers reported screening a greater proportion of clients for early psychosis, referring a greater number of clients to specialty services, and feeling more confident in their ability to respond to clients with early psychosis. Increases in confidence following attendance were associated with corresponding increases in screening behaviour. Conclusions: The results suggest that outreach campaigns designed to enhance community providers' knowledge about early psychosis assessment and resources may be effective in promoting screening, referrals, and confidence in managing psychosis. Gains in provider confidence may contribute to increases in screening. Given the lack of control group and relatively short follow‐up period, more research is needed to determine the effects of early psychosis educational events and the mechanisms by which they may promote successful treatment delivery for young people in need. [ABSTRACT FROM AUTHOR]

Aim: Increasing evidence points to the value of coordinated specialty care (CSC) for early intervention in psychotic disorders. This report characterizes clinical and socio‐demographic features of patients at CSC programs in Massachusetts (MA), assessed by a standardized battery incorporated into "real‐world" clinical care. Methods: The MA psychosis network for early treatment developed a pilot battery to coordinate assessments across six CSC clinics. Programs reported baseline, 6‐month, and 12‐month data from a sample of 287 patients with intake dates ranging from April 2015 to December 2020. Results: Patients showed improvements in functioning, emergency service use and several symptom domains at 6 and 12 months. Missing data proved to be a limitation. Conclusions: Patients improved on several meaningful domains within the first year of CSC treatment. Future implementation efforts in cross‐program data collection should consider strategies to circumvent limitations related to heterogeneity between clinics, patient discharge and clinics' capacity for data collection. [ABSTRACT FROM AUTHOR]

Objectives: Affective and psychotic features overlap considerably in bipolar I disorder, complicating efforts to determine its etiology and develop targeted treatments. In order to clarify whether mechanisms are similar or divergent for bipolar disorder with psychosis (BDP) and bipolar disorder with no psychosis (BDNP), neurobiological profiles for both the groups must first be established. This study examines white matter structure in the BDP and BDNP groups, in an effort to identify portions of white matter that may differ between the bipolar and healthy groups or between the bipolar subgroups themselves. Methods: Diffusion‐weighted imaging data were acquired from participants with BDP (n = 45), BDNP (n = 40), and healthy comparisons (HC) (n = 66). Fractional anisotropy (FA), radial diffusivity (RD), and spin distribution function (SDF) values indexing white matter diffusivity or spin density were calculated and compared between the groups. Results: In comparisons between both the bipolar groups and HC, FA (FDR < 0.00001) and RD (FDR = 0.0037) differed minimally, in localized portions of the left cingulum and corpus callosum, while reductions in SDF (FDR = 0.0002) were more widespread. The bipolar subgroups did not differ from each other on FA, RD, or SDF metrics. Conclusions: Together, these results demonstrate a novel profile of white matter differences in bipolar disorder and suggest that this white matter pathology is associated with the affective disturbance common to those with bipolar disorder rather than the psychotic features unique to some. The white matter alterations identified in this study may provide substrates for future studies examining specific mechanisms that target affective domains of illness. [ABSTRACT FROM AUTHOR]

Aim: Family interventions are a core component of first‐episode psychosis (FEP) treatment; however, low implementation rates are consistently reported. As such, work is needed to understand the factors impacting real‐world treatment delivery. The present paper describes the implementation of the McFarlane‐model multifamily psychoeducational groups (MFG) in established FEP early intervention programs within a single state. The aims were to examine (a) training participation and implementation of MFG, (b) barriers and facilitators to implementation, and (c) modifications made to MFG. Methods: Practitioners from six established FEP early intervention programs received in‐person training and ongoing consultation in MFG. Training participation data were obtained via attendance and implementation outcomes were obtained from practitioner reports. Fifteen months following the initial training, practitioners reported on clinic‐specific barriers, facilitators, and modifications across four categories (context, intervention, practitioner, and recipient). Results: Twenty‐three practitioners across six clinics received in‐person training and were offered ongoing consultation to support implementation. Difficulties in starting MFG were salient as the earliest group was run 7 months after the initial training, thereby resulting in low overall frequency of groups. A number of barriers spanning context, intervention, practitioner, and recipient domains were noted, the majority of which were clinic‐specific. Despite challenges, practitioners identified several facilitators and made modifications to the intervention and its delivery in service of implementation. Conclusions: Results from this implementation case study highlighted the challenges of delivering MFG in real‐world FEP early intervention programs. Further, this paper emphasizes the value in identifying and addressing clinic‐specific factors when implementing MFG. [ABSTRACT FROM AUTHOR]

"Resting‐state" functional magnetic resonance imaging (rs‐fMRI) is widely used to study brain connectivity. So far, researchers have been restricted to measures of functional connectivity that are computationally efficient but undirected, or to effective connectivity estimates that are directed but limited to small networks. Here, we show that a method recently developed for task‐fMRI—regression dynamic causal modeling (rDCM)—extends to rs‐fMRI and offers both directional estimates and scalability to whole‐brain networks. First, simulations demonstrate that rDCM faithfully recovers parameter values over a wide range of signal‐to‐noise ratios and repetition times. Second, we test construct validity of rDCM in relation to an established model of effective connectivity, spectral DCM. Using rs‐fMRI data from nearly 200 healthy participants, rDCM produces biologically plausible results consistent with estimates by spectral DCM. Importantly, rDCM is computationally highly efficient, reconstructing whole‐brain networks (>200 areas) within minutes on standard hardware. This opens promising new avenues for connectomics. [ABSTRACT FROM AUTHOR]

Background: Neurovascular abnormalities are relevant to the pathophysiology of bipolar disorder (BD), which can be assessed using cerebral blood flow (CBF) imaging. CBF alterations have been identified in BD, but studies to date have been small and inconclusive. We aimed to determine cortical gray matter CBF (GM‐CBF) differences between BD and healthy controls (HC) and to identify relationships between CBF and clinical or cognitive measures. Methods: Cortical GM‐CBF maps were generated using Pseudo‐Continuous Arterial Spin Labeling (pCASL) for 109 participants (BD, n = 61; HC, n = 48). We used SnPM13 to perform non‐parametric voxel‐wise two‐sample t‐tests comparing CBF between groups. We performed multiple linear regression to relate GM‐CBF with clinical and cognitive measures. Analysis was adjusted for multiple comparisons with 10,000 permutations. Significance was set at a voxel level threshold of P <.001 followed by AlphaSim cluster‐wise correction of P <.05. Results: Compared to HCs, BD patients had greater GM‐CBF in the left lateral occipital cortex, superior division and lower CBF in the right lateral occipital, angular and middle temporal gyrus. Greater GM‐CBF in the left lateral occipital cortex correlated with worse working memory, verbal memory, attention and speed of processing. We found using voxel‐wise regression that decreased gray matter CBF in the bilateral thalamus and cerebellum, and increased right fronto‐limbic CBF were associated with worse working memory. No clusters were associated with clinical variables after FDR correction. Conclusions: Cortical GM‐CBF alterations are seen in BD and may be related to cognitive function, which suggest neurovascular unit dysfunction as a possible pathophysiologic mechanism. [ABSTRACT FROM AUTHOR]

Objectives: Smooth pursuit eye movement deficits are an established psychosis biomarker across schizophrenia, schizoaffective and psychotic bipolar disorder (BPwP). Whether smooth pursuit deficits are also seen in bipolar disorder without psychosis (BPwoP) is unclear. Here we present data from the Psychosis and Affective Research Domains and Intermediate Phenotypes (PARDIP) study comparing bipolar patients with and without psychotic features. Methods: Probands with BPwP (N = 49) and BPwoP (N = 36), and healthy controls (HC, N = 71) performed eye tracking tasks designed to evaluate specific sensorimotor components relevant for pursuit initiation and pursuit maintenance. Results: While BPwoP did not differ from either BPwP or HC on initial eye acceleration, they performed significantly better than BPwP on early (P <.01) and predictive (P =.02) pursuit maintenance measures, both without differing from HC. BPwP were impaired compared to HC on initial eye acceleration, and on early and predictive pursuit maintenance (all P <.01). In contrast to the three pursuit measures, BPwP and BPwoP were both impaired on general neurocognitive assessments in relation to HC (both P <.001), without a significant difference between the two bipolar patient groups. Conclusions: Our findings support the model that impairments of sensorimotor and cognitive processing as required for early and later predictive smooth pursuit maintenance are relatively specific to those bipolar patients with a history of psychosis. This suggests that the neural circuitry for developing feed‐forward predictive models for accurate pursuit maintenance is associated with the occurrence of psychotic features in bipolar patients. In contrast, generalized neuropsychological impairments did not differentiate the two bipolar patient groups. [ABSTRACT FROM AUTHOR]

Objectives: We sought to evaluate whether dynamic Arterial Spin Labeling (dASL), a novel quantitative technique robust to artifacts and noise that especially arise in inferior brain regions, could characterize neural substrates of BD pathology and symptoms. Methods: Forty‐five subjects (19 BD patients, 26 controls) were imaged using a dASL sequence. Maps of average perfusion, perfusion fluctuation, and perfusion connectivity with anterior cingulate cortex (ACC) were derived. Patient symptoms were quantified along four symptom dimensions determined using factor analysis of the subjects from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (BSNIP) study. Maps of the perfusion measures were compared between BD patients and controls and correlated with the symptom dimensions in the BD patients only by voxel‐level and region‐level analyses. Results: BD patients exhibited (i) significantly increased perfusion fluctuations in the left fusiform and inferior temporal regions (P =.020, voxel‐level corrected) and marginally increased perfusion fluctuations in the right temporal pole and inferior temporal regions (P =.063, cluster‐level corrected), (ii) significantly increased perfusion connectivity between ACC and the occipitoparietal cortex (P =.050, cluster‐level corrected). In BD patients, positive symptoms were negatively associated with ACC perfusion connectivity to the right orbitofrontal and superior frontal regions (P =.002, cluster‐level corrected) and right orbitofrontal and inferior frontal regions (P =.023, cluster‐level corrected). Conclusion: The abnormal perfusion fluctuations and connectivity alterations may underlie the mood fluctuations and cognitive and emotional dysregulation that characterize BD. [ABSTRACT FROM AUTHOR]

Aim: While the course of psychopathology has been explored from an index mental health diagnosis onwards, there are few detailed, prospective studies of the occurrence of clinical psychopathology in youth with familial risk for severe mental illnesses such as psychosis. We sought to describe the appearance of Axis I psychopathology in a unique sample of adolescents with a family history of schizophrenia (FHR). Methods: One hundred and sixty two first‐ and second‐degree relatives (mean age 15.7 ± 3.6; range 8‐25) of probands with schizophrenia or schizoaffective disorder were assessed at baseline and annual intervals for up to 3 years, focusing on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM‐IV‐TR) Axis I psychopathology. Results: Fourteen individuals (8.6%) developed a psychotic disorder. One hundred and five subjects (65%) met criteria for an Axis I disorder over the course of the study, the most common of which was a depressive episode (40 subjects; 25%). Of the 148 individuals who did not develop psychosis, 91 (61%) had one or more Axis I disorders compared with 10/14 converters who had a comorbid Axis I disorder (71%). Ordered by increasing age of onset, diagnoses included cognitive and externalizing disorders, anxiety disorders, affective disorders, substance use disorders and psychotic disorders. Conclusions: In addition to an elevated risk of psychosis, young FHR relatives manifest a broad range of non‐psychotic Axis I psychopathology in childhood and adolescence. This breadth of diagnoses has implications for the structure and function of mental health services for young people. [ABSTRACT FROM AUTHOR]

Despite a growing number of reports about alterations in intrinsic/resting brain activity observed in patients with psychotic disorders, their relevance to well‐established cognitive control deficits in this patient group is not well understood. Totally 88 clinically stabilized patients with a psychotic disorder and 50 healthy controls participated in a resting‐state magnetic resonance imaging study (rs‐MRI) and performed an antisaccade task in the laboratory to assess voluntary inhibitory control ability. Deficits on this task are a well‐established biomarker across psychotic disorders as we found in the present patient sample. First, regional cerebral function was evaluated by measuring the amplitude of low frequency fluctuations (ALFF) in rs‐MRI BOLD signals. We found reduced ALFF in patients in regions known to be relevant to antisaccade task performance including bilateral frontal eye fields (FEF), supplementary eye fields (SEF) and thalamus. Second, areas with ALFF alterations were used as seed areas in whole‐brain functional connectivity (FC) analysis. Altered FC was observed in a fronto‐thalamo‐parietal network that was associated with inhibition error rate in patients but not in controls. In contrast, faster time to generate a correct antisaccade was associated with FC in FEF and SEF in controls but this effect was not seen in patients. These findings establish a behavioral relevance of resting‐state fMRI findings in psychotic disorders, and extend previous reports of alterations in fronto‐thalamo‐parietal network activation during antisaccade performance seen in task‐based fMRI studies. [ABSTRACT FROM AUTHOR]

Individuals with psychosis have been reported to show either reduced or augmented brain responses under seemingly similar conditions. It is likely that inconsistent baseline-adjustment methods are partly responsible for this discrepancy. Using steady-state stimuli during a pro/antisaccade task, this study addressed the relationship between nonspecific and stimulus-related neural activity, and how these activities are modulated as a function of cognitive demands. In 98 psychosis probands (schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis), neural activity was assessed during baseline and during a 5-s period in preparation for the pro/antisaccade task. To maximize the ability to identify meaningful differences between psychosis subtypes, analyses were conducted as a function of subgrouping probands by standard clinical diagnoses and neurobiological features. These psychosis 'biotypes' were created using brain-based biomarkers, independent of symptomatology (Clementz et al., ). Psychosis probands as a whole showed poor antisaccade performance and diminished baseline oscillatory phase synchrony. Psychosis biotypes differed on both behavioral and brain measures, in ways predicted from Clementz et al. (). Two biotype groups showed similarly deficient behavior and baseline synchrony, despite diametrically opposed neural activity amplitudes. Another biotype subgroup was more similar to healthy individuals on behavioral and brain measures, despite the presence of psychosis. This study provides evidence that (a) consideration of baseline levels of activation and synchrony will be essential for a comprehensive understanding of neural response differences in psychosis, and (b) distinct psychosis subgroups exhibit reduced versus augmented intrinsic neural activity, despite cognitive performance and clinical similarities. [ABSTRACT FROM AUTHOR]

Functional magnetic resonance imaging (fMRI) studies have shown altered brain dynamic functional connectivity (DFC) in mental disorders. Here, we aim to explore DFC across a spectrum of symptomatically-related disorders including bipolar disorder with psychosis (BPP), schizoaffective disorder (SAD), and schizophrenia (SZ). We introduce a group information guided independent component analysis procedure to estimate both group-level and subject-specific connectivity states from DFC. Using resting-state fMRI data of 238 healthy controls (HCs), 140 BPP, 132 SAD, and 113 SZ patients, we identified measures differentiating groups from the whole-brain DFC and traditional static functional connectivity (SFC), separately. Results show that DFC provided more informative measures than SFC. Diagnosis-related connectivity states were evident using DFC analysis. For the dominant state consistent across groups, we found 22 instances of hypoconnectivity (with decreasing trends from HC to BPP to SAD to SZ) mainly involving post-central, frontal, and cerebellar cortices as well as 34 examples of hyperconnectivity (with increasing trends HC through SZ) primarily involving thalamus and temporal cortices. Hypoconnectivities/hyperconnectivities also showed negative/positive correlations, respectively, with clinical symptom scores. Specifically, hypoconnectivities linking postcentral and frontal gyri were significantly negatively correlated with the PANSS positive/negative scores. For frontal connectivities, BPP resembled HC while SAD and SZ were more similar. Three connectivities involving the left cerebellar crus differentiated SZ from other groups and one connection linking frontal and fusiform cortices showed a SAD-unique change. In summary, our method is promising for assessing DFC and may yield imaging biomarkers for quantifying the dimension of psychosis. Hum Brain Mapp 38:2683-2708, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The characterization of neurodevelopmental aspects of brain alterations require neuroimaging methods that reflect correlates of neurodevelopment, while being robust to other progressive pathological processes. Newly developed neuroimaging methods for measuring geometrical features of the white matter fall exactly into this category. Our recent work shows that such features, measured in the anterior corpus callosum in diffusion MRI data, correlate with psychosis symptoms in patients with adolescent onset schizophrenia and subside a reversal of normal sexual dimorphism. Here, we test the hypothesis that similar developmental deviations will also be present in nonpsychotic subjects at familial high risk (FHR) for schizophrenia, due to genetic predispositions. Demonstrating such changes would provide a strong indication of neurodevelopmental deviation extant before, and independent of pathological changes occurring after disease onset. We examined the macrostructural geometry of corpus callosum white matter in diffusion MRI data of 35 non-psychotic subjects with genetic (familial) risk for schizophrenia, and 26 control subjects, both male and female. We report a reversal of normal sexual dimorphism in callosal white matter geometry consistent with recent results in adolescent onset schizophrenia. This pattern may be indicative of an error in neurogenesis and a possible trait marker of schizophrenia. [ABSTRACT FROM AUTHOR]

Disrupted sensory processing is a core feature of psychotic disorders. Auditory paired stimuli ( PS) evoke a complex neural response, but it is uncertain which aspects reflect shared and/or distinct liability for the most common severe psychoses, schizophrenia ( SZ) and psychotic bipolar disorder ( BDP). Evoked time-voltage/time-frequency domain responses quantified with EEG during a typical PS paradigm (S1-S2) were compared among proband groups ( SZ [ n = 232], BDP [181]), their relatives ( SZrel [259], BDPrel [220]), and healthy participants ( H [228]). Early S1-evoked responses were reduced in SZ and BDP, while later/S2 abnormalities showed SZ/ SZrel and BDP/ BDPrel specificity. Relatives' effects were absent/small despite significant familiality of the entire auditorineural response. This pattern suggests general and divergent biological pathways associated with psychosis, yet may reflect complications with conditioning solely on clinical phenomenology. [ABSTRACT FROM AUTHOR]

Aim Accurate prediction of which high-risk individuals will go on to develop psychosis would assist early intervention and prevention paradigms. We sought to review investigations of prospective psychosis prediction based on markers and variables examined in longitudinal familial high-risk ( FHR) studies. Methods We performed literature searches in Med Line, Pub Med and PsycINFO for articles assessing performance characteristics of predictive clinical tests in FHR studies of psychosis. Studies were included if they reported on one or more predictive variables in subjects at FHR for psychosis. We complemented this search strategy with references drawn from articles, reviews, book chapters and monographs. Results Across generations of FHR projects, predictive studies have investigated behavioural, cognitive, psychometric, clinical, neuroimaging and other markers. Recent analyses have incorporated multivariate and multi-domain approaches to risk ascertainment, with generally modest results. Conclusions Although a broad range of risk factors has been identified, no individual marker or combination of markers can at this time enable accurate prospective prediction of emerging psychosis for individuals at FHR. We outline the complex and multi-level nature of psychotic illness, the myriad of factors influencing its development, and methodological hurdles to accurate and reliable prediction. Prospects and challenges for future generations of FHR studies are discussed in the context of early detection and intervention strategies. [ABSTRACT FROM AUTHOR]

Objectives Bipolar I disorder is a disabling illness affecting 1% of people worldwide. Family and twin studies suggest that psychotic bipolar disorder ( BDP) represents a homogeneous subgroup with an etiology distinct from non-psychotic bipolar disorder ( BDNP) and partially shared with schizophrenia. Studies of auditory electrophysiology [e.g., paired-stimulus and oddball measured with electroencephalography ( EEG)] consistently report deviations in psychotic groups (schizophrenia, BDP), yet such studies comparing BDP and BDNP are sparse and, in some cases, conflicting. Auditory EEG responses are significantly reduced in unaffected relatives of psychosis patients, suggesting that they may relate to both psychosis liability and expression. Methods While 64-sensor EEGs were recorded, age- and gender-matched samples of 70 BDP, 35 BDNP {20 with a family history of psychosis [ BDNP(+)]}, and 70 psychiatrically healthy subjects were presented with typical auditory paired-stimuli and auditory oddball paradigms. Results Oddball P3b reductions were present and indistinguishable across all patient groups. P2s to paired stimuli were abnormal only in BDP and BDNP(+). Conversely, N1 reductions to stimuli in both paradigms and P3a reductions were present in both BDP and BDNP(−) groups but were absent in BDNP(+). Conclusions Although nearly all auditory neural response components studied were abnormal in BDP, BDNP abnormalities at early- and mid-latencies were moderated by family psychosis history. The relationship between psychosis expression, heritable psychosis risk, and neurophysiology within bipolar disorder, therefore, may be complex. Consideration of such clinical disease heterogeneity may be important for future investigations of the pathophysiology of major psychiatric disturbance. [ABSTRACT FROM AUTHOR]

Individuals with schizophrenia ( SZ) or bipolar disorder with psychosis ( BPP) may share neurophysiological abnormalities as measured in auditory paired-stimuli paradigms with electroencephalography ( EEG). Such investigations have been limited, however, by quantifying only event-related potential peaks and/or broad frequency bands at limited scalp locations without considering possible mediating factors (e.g., baseline differences). Results from 64-sensor EEG collected in 180 age- and gender-matched participants reveal (i) accentuated prestimulus gamma oscillations and (ii) reduced P2 amplitudes and theta/alpha oscillations to S1 among participants with both SZ and BPP. Conversely, (iii) N1s in those with SZ to S1 were reduced compared to healthy volunteers and those with BPP, whereas (iv) beta range oscillations 200-300 ms following S2 were accentuated in those with BPP but not those with SZ. Results reveal a pattern of both unique and shared neurophysiological phenotypes occurring within major psychotic diagnoses. [ABSTRACT FROM AUTHOR]

Cortical and central white matter (WM) volumes were measured to assess short- and long-range connectivity in autism, respectively. Subjects included 23 boys with autism and 23 matched controls, all without intellectual disability. Magnetic resonance imaging data obtained at 1.5 T were analyzed using BRAINS2 software (University of Iowa, Iowa City, IA, USA). Central WM volume was quantified by subtracting cortical from supratentorial WM volumes. Reduced central WM volume was observed in the autism group. IQ was higher in controls with no observed correlations between WM volumes and IQ. This preliminary evidence of reduced central WM volume in autism suggests abnormal long-range connectivity. [ABSTRACT FROM AUTHOR]

The purpose of this study is to examine the association between parental socio-economic status (SES) and childhood neurocognition and behavior in children with chromosome 22q11.2 deletion syndrome (22q11DS). Although undoubtedly, the deletion of genes in the 22q11.2 interval is primarily responsible for the psychological manifestations, little is known about the role of the environment in either mitigating or contributing to these problems. We examined the association of parental socio-economic status (SES) with cognition and behavior in children with 22q11DS ( n = 65) and matched healthy control subjects ( n = 52), since SES is a component of family resources. We found that in children with 22q11DS, higher SES correlated with better overall functioning ( p < .01) and social skills ( p < .01), and less frequent oppositional defiant behavior ( p < .001). These findings were in contrast to the control subjects in whom SES correlated with cognition and achievement, but not behavior. Our results indicate that environmental factors influence the behavioral phenotype in children with 22q11DS, providing a framework for developing appropriate interventions. As such, genetic counseling for families with 22q11DS may include consideration of family resources and inclusion of other health professionals, such as social workers, to explore with the family available social supports and resources. [ABSTRACT FROM AUTHOR]

Objective: Children and adolescents with schizophrenia share a similar pattern of phenomenological, genetic and cognitive abnormalities to adults with schizophrenia. However, an early-onset of schizophrenia (EOS) (prior to 18 years of age) is associated with a higher frequency of risk indicators associated with schizophrenia (e.g. developmental delays and familial spectrum disorders) and a worse long-term outcome. This overview examines recent research on the neurobiological alterations, possible causes, developmental trajectory and treatment of EOS and attempts to identify gaps in the field. Method: The authors provide a selective review of major findings from genetics, neuroimaging and treatment studies of pediatric schizophrenia that were presented at a workshop sponsored by the National Institute of Mental Health. These data are synthesized in conjunction with preclinical studies into a model of the pathophysiology of EOS. Results: EOS is associated with a high frequency of cytogenetic abnormalities (e.g. velocardiofacial syndrome, sex chromosome anomalies) and other rare denovo chromosomal aberrations. Brain imaging research in adolescents with EOS has revealed a progressive loss of cortical grey matter post-onset of psychosis and subtle abnormalities in white matter microstructure. Although EOS patients are more likely to be treatment-refractory than their adult counterparts, there are substantial data that this subgroup is particularly responsive to clozapine. Conclusions: Genetic or environmental factors operating during adolescence that reduce frontal capacity might contribute to an EOS in susceptible individuals. Additional longitudinal studies of adolescents with schizophrenia are needed to better understand the relationship between structural changes in fronto-limbic regions, stress responsivity, and cognitive and neurochemical development. [ABSTRACT FROM AUTHOR]

Aims: Individuals at risk for developing schizophrenia (SZ) in the future frequently exhibit subtle behavioural and neurobiological abnormalities in their childhood. A better understanding of the role of these abnormalities in predicting later onset of ‘prodromal’ symptoms or psychosis may help in early identification of SZ. Methods: In an ongoing prospective follow-up study of young genetically at-risk relatives of patients with SZ, we studied the prevalence of problems in premorbid social adjustment and childhood psychopathology and examined their relationship with the presence and progression of ‘prodromal’ symptoms of SZ. Results: Growth curve analyses showed that ‘prodromal’ symptoms, as measured by the Scale of ‘Prodromal’ Symptoms, increased during follow-up. Premorbid maladjustment and childhood behavioural disturbances were cross-sectionally correlated broadly with ‘prodromal’ symptomatology scores. Longitudinal analyses revealed that behavioural disturbances, but not childhood maladjustment at baseline, significantly predicted increases in ‘prodromal’ symptomatology during the 2-year study period. Conclusion: Premorbid behavioural disturbance and maladjustment may predict the later emergence of ‘prodromal’ symptoms. ‘Prodromal’ symptoms in young at-risk relatives may define a subgroup worthy of follow-up into the age of risk for psychosis in order to cost-effectively characterize the predictors of psychotic symptoms and SZ. [ABSTRACT FROM AUTHOR]

Objectives: Functional and postmortem studies suggest that the orbitofrontal cortex (OFC) is involved in the pathophysiology of bipolar disorder (BD). This anatomical magnetic resonance imaging (MRI) study examined whether BD patients have smaller OFC gray matter volumes compared to healthy comparison subjects (HC). Methods: Twenty-eight BD patients were compared to 28 age- and gender-matched HC. Subjects underwent a 1.5T MRI with 3D spoiled gradient recalled acquisition. Total OFC and medial and lateral subdivisions were manually traced by a blinded examiner. Images were segmented and gray matter volumes were calculated using an automated method. Results: Analysis of covariance, with intracranial volume as covariate, showed that BD patients and HC did not differ in gray matter volumes of total OFC or its subdivisions. However, total OFC gray matter volume was significantly smaller in depressed patients (n = 10) compared to euthymic patients (n = 18). Moreover, total OFC gray matter volumes were inversely correlated with depressive symptom intensity, as assessed by the Hamilton Depression Rating Scale. OFC gray matter volumes were not related to lithium treatment, age at disease onset, number of episodes, or family history of mood disorders. Conclusions: Our results suggest that abnormal OFC gray matter volumes are not a pervasive characteristic of BD, but may be associated with specific clinical features of the disorder. [ABSTRACT FROM AUTHOR]

Background: Increased susceptibility for developing alcohol dependence (AD) may be related to structural and functional differences in brain circuits that influence social cognition and more specifically, theory of mind (ToM). Alcohol dependent individuals have a greater likelihood of having deficits in social skills and greater social alienation. These characteristics may be related to inherited differences in the neuroanatomical network that comprises the social brain. Methods: Adolescent/young adult participants from multiplex AD families and controls ( n = 16) were matched for gender, age, IQ, education, and handedness and administered the Eyes Task of Baron-Cohen during functional magnetic resonance imaging (fMRI). Results: High-risk (HR) subjects showed significantly diminished blood oxygen level dependent (BOLD) response in comparison with low-risk control young adults in the right middle temporal gyrus (RMTG) and the left inferior frontal gyrus (LIFG), areas that have previously been implicated in ToM tasks. Conclusions: Offspring from multiplex families for AD may manifest one aspect of their genetic susceptibility by having a diminished BOLD response in brain regions associated with performance of ToM tasks. These results suggest that those at risk for developing AD may have reduced ability to empathize with others’ state of mind, possibly resulting in diminished social skill. [ABSTRACT FROM AUTHOR]

Sanches M, Roberts RL, Sassi RB, Axelson D, Nicoletti M, Brambilla P, Hatch JP, Keshavan MS, Ryan ND, Birmaher B, Soares JC. Developmental abnormalities in striatum in young bipolar patients: a preliminary study.Bipolar Disord 2005: 7: 153–158.© Blackwell Munksgaard, 2005Anatomical abnormalities in the basal ganglia of adult mood disorder patients have been reported. To investigate whether these abnormalities are present early in illness course, we compared the volume of striatal structures in young bipolar patients and healthy controls.Brain magnetic resonance images of 15 children and adolescents who met DSM-IV criteria for bipolar disorders and 21 healthy controls were obtained. Measurements were performed manually, by trained evaluators, who were blind to subjects’ diagnosis. The volumes of caudate and putamen were compared in patients and controls.The volumes of striatal structures were not significantly different in patients and controls (ANCOVA, p > 0.05). However, we found a significant inverse relationship between age and the volumes of left caudate (r = −0.72, p < 0.01), right caudate (r = −0.66, p = 0.02) and left putamen (r = −0.71, p = 0.01) in bipolar patients, not present in healthy controls.Abnormalities in striatal development may be involved in the pathophysiology of bipolar disorder. [ABSTRACT FROM AUTHOR]

Aim: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS)., Methods: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences., Results: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS., Conclusions: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses., (© 2023 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Background: In adults, prefrontal, thalamic, and cerebellar brain injury is associated with excessive ethanol intake. As these brain structures are actively maturing during adolescence, we hypothesized that subjects with adolescent-onset alcohol use disorders, compared with control subjects, would have smaller brain volumes in these areas. Thus, we compared prefrontal-thalamic-cerebellar measures of adolescents and young adults with adolescent-onset alcohol use disorders (AUD, defined as DSM-IV alcohol dependence or abuse) with those of sociodemographically similar control subjects., Methods: Magnetic resonance imaging was used to measure prefrontal cortex, thalamic, and cerebellar volumes in 14 subjects (eight males, six females) with an AUD (mean age, 17.0+/-2.1 years) and 28 control subjects (16 males, 12 females; 16.9+/-2.3 years). All AUD subjects were recruited from substance abuse treatment programs and had comorbid mental disorders., Results: Subjects with alcohol use disorders had smaller prefrontal cortex and prefrontal cortex white matter volumes compared with control subjects. Right, left, and total thalamic, pons/brainstem, right and left cerebellar hemispheric, total cerebellar, and cerebellar vermis volumes did not differ between groups. There was a significant sex-by-group effect, indicating that males with an adolescent-onset AUD compared with control males had smaller cerebellar volumes, whereas the two female groups did not differ in cerebellar volumes. Prefrontal cortex volume variables significantly correlated with measures of alcohol consumption., Conclusions: These findings suggest that a smaller prefrontal cortex is associated with early-onset drinking in individuals with comorbid mental disorders. Further studies are warranted to examine if a smaller prefrontal cortex represents a vulnerability to, or a consequence of, early-onset drinking.